Adverse events in children and adolescents undergoing allergen immunotherapy for respiratory allergies—Report from the Allergen Immunotherapy Adverse Events Registry (ADER), a European Academy of Allergy and Clinical Immunology taskforce

Abstract Background Although it has been shown that allergen immunotherapy (AIT) is well‐tolerated in children, systematic and prospective surveillance of AIT safety in real life settings is needed. Methods The multinational Allergen Immunotherapy Adverse Events Registry (ADER) was designed to address AIT safety in real life clinical practice. Data on children ≤18 years old with respiratory allergies undergoing AIT were retrieved. Patient‐ and AIT‐related features were collected and analyzed. The characteristics of adverse events (AE) and risk factors were evaluated. Results A total of 851 patients, 11.3 ± 3.4 years old, with rhinitis only (47.6%); asthma and rhinitis (44.5%); asthma (7.9%), receiving 998 AIT courses were analyzed. Sublingual immunotherapy (SLIT) accounted for 51% of the courses. In 84.5% of patients only one AIT treatment was prescribed. Pollen was the most frequent sensitizer (57.1%), followed by mites (53.4%), molds (18.2%) and epithelia (16.7%). Local and systemic AEs were reported in 85 patients (9.9%). Most AEs (83.1%) were mild and occurred in <30 min (87%). Respiratory and cutaneous symptoms were more frequent. Only 4 patients (0.47%) had severe AE (none after 6 weeks of maintenance). The risk of AE was higher in patients undergoing SCIT. Conclusions AIT is safe and well tolerated in children and adolescents with respiratory allergies in real‐life clinical practice. Though SCIT is more prone to AE compared to SLIT, overall severe reactions are rare and occur during build‐up and early maintenance.


| INTRODUCTION
Allergen immunotherapy (AIT) is currently the only disease modifying treatment option for children and adults with IgE-mediated allergic disorders. Both subcutaneous (SCIT) and sublingual (SLIT) routes are proven to be effective in providing short-and long-term benefits in allergic patients that may persist after discontinuation. [1][2][3] It has been shown that allergen immunotherapy in children is well-tolerated, but there are still concerns regarding safety. [4][5][6][7][8] Even though few observational studies and RCTs have evaluated adverse events (AE) due to AIT, there is a need for systematically and prospectively documenting these AE, in the context of an AIT registry. [9][10][11][12][13] Such a registry (Allergen Immunotherapy Adverse Reactions Registry -ADER) has been established with the support of the European Academy of Allergy and Clinical Immunology. 14 Moreover, it is important to identify and highlight factors that may increase the risk of AE. Although several previous reports have assessed several risk factors associated with AE during AIT, data regarding the pediatric population are lacking. 9,[15][16][17][18] In this report, we describe the characteristics and evaluate risk factors for adverse reactions in children and adolescents with allergic rhinoconjunctivitis and/or asthma who underwent AIT for pollen, mites, molds and/or epithelia.

| METHODOLOGY
The overall methodology of the ADER registry has been described. 14 In short, ADER is a prospective, observational, multicenter, web- and Turkey (TR). The data were collected through three questionnaires developed by the ADER Task Force (additional questions were added to assess local reactions). 14 AEs were recorded according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology. 19 The Research Electronic Data Capture (REDCap) electronic platform was used to ensure safe uploading and storage of the registry. 20

| Ethics
ADER complies with national and European ethical and regulatory requirements, including data protection. Each NC was responsible for obtaining study approval from its corresponding national or local independent Ethics Committee.

| Study population and adverse event recording
Among subjects registered in ADER, we have retrieved in this study children and adolescents ≤18 years old with allergic rhinitis and/or conjunctivitis and/or asthma who underwent SCIT or SLIT for mites, pollens, molds (alternaria) and/or epithelia. A total of 851 patients receiving 998 courses of AIT were included. They were 11.3 � 3.4 years old and most of them were males (63.2%). There were 480 (56.4%) children (n = 52 preschool, aged ≤6 years old) and 371 (43.6%) adolescents. Data on sensitization, past medical history and allergy history, current treatments, and characteristics of the current AIT course(s) were collected from the patient's clinical files.
Patients suffered from allergic rhinitis (AR) alone in 47.6% of cases, AR and asthma in 44.5% and asthma only in 7.9%. Poly-sensitization was observed in 53% of patients. Pollens were the most frequent sensitizer in 57.1%, followed by mites (53.4%), molds (18.2%) and epithelia (16.7%). SLIT accounted for 51% of all treatments [n = 506 courses (drops in 485; tablets in 20; 1 course unspecified)], prescribed in 446 (52.5%) patients, while SCIT was prescribed in 405 patients (492 courses). In the majority of cases (84.4%) only one AIT course was administered, two treatment courses in 14.2% and more than two in only 12 patients (Table 1). Non-allergic comorbidities were also recorded but were rare: gastrointestinal disease in 2 cases, dermatologic in 1 case, psychiatric in 3 and rheumatic and pulmonary conditions in 1 case each. Both systemic and local AE that occurred during AIT were recorded in detail. The severity of AE was classified (a) according to the Muller grade classification system, 21 and (b) as mild, moderate and severe. 22 We also recorded the phase when the AEs occurred (build-up or maintenance), treatment, the time of onset and resolution, final outcomes and possible modification of the treatment course. Systemic adverse reactions were recorded using MeDRA. 19 Local reactions related to SCIT or SLIT were collected and classified as (a) local skin symptoms, (b) large local cutaneous reactions, (c) local mouth symptoms, and (d) oral edema.  Table S1). dosing and one in maintenance; 2 were receiving AIT to grass, one to mites and one to parietaria; 3 had allergic rhinitis, while 1 had asthma and rhinitis). A detailed description of the severe cases is shown in Table 3.

| Severity and treatment of adverse events
AEs were recorded mostly during build-up and early maintenance. Most AEs were reported during up-dosing (52.7%) or early (4-6 weeks) maintenance (45.7%) compared to later maintenance (>6 weeks) (1.6%). The frequency of AE was marginally higher during the build-up compared to early maintenance for both SCIT and SLIT treatments (p = 0.051). There was no difference regarding severity between build-up and early maintenance; however, no severe reactions were observed after 6 weeks of maintenance. Two reactions observed in later maintenance were associated with SLIT treatments and were mild/moderate (Table 4).

| Time interval of onset and duration of AE
The onset time was also grouped into three categories:  (Table 5).

| Risk factors for adverse events
Univariate analysis was performed for the following variables: age, sex, allergic condition, comorbidities, number of treatments, sensitization

T A B L E 3
Characteristics of the patients with severe AE.  Table S4).

| DISCUSSION
This is the first report on the real-life safety of AIT for respiratory allergy from a multinational registry. Adverse events due to AIT in children have been mostly assessed in either the context of clinical trials or surveys. 9,10,23,24 The EAACI first international retrospective survey recently evaluated AIT practical aspects and safety during the COVID-19 pandemic, generating important real world data. The report showed no concerns regarding AIT tolerability. 33 The role of registries as a robust, real-world data gathering tool has been highlighted recently. 11 BRIT, a UK-based prospective registry, has reported outcomes from the UK National Health System on the efficacy and safety of AIT and other immunomodulatory treatments for chronic spontaneous urticaria, reflecting real-life clinical practice. 12,13 In contrast, ADER encompasses a wider picture, mirroring how AIT works in 8 different centers in real life with all the expected heterogeneity, making this registry a valuable additional resource of real world evidence. Considering that ADER is focused on AIT safety, our results cover the full spectrum of AE characteristics and describe in detail all AE occurred during AIT treatment. Moreover, the dataset offers the possibility to assess factors that can lead to AE.
Our results are reassuring in that both SCIT and SLIT treatments are well tolerated in children and adolescents. AEs were recorded in overall about 10% of patients. The range of local and systemic reactions reported from previous studies is as low as 1.5% 23 up to 17.9%. [25][26][27][28] This is not surprising, taking into account that patient selection, type of product, adjuvant and route of administration as well as intensity of follow-up may affect safety outcomes and vary considerably. ADER is a multicenter registry that includes patients from 8 countries with different characteristics, a wide spectrum of AIT products and administration protocols. In fact, within ADER, the range of AE ratios between countries was very wide, although the higher proportions were observed in countries with small sample sizes.
Unsurprisingly, significantly less AEs were observed with SLIT than with SCIT. 5 In fact, up to 90% of all AEs occurred during SCIT, while the ratio of patients suffering from an AE was more than 3 times lower in SLIT (4.9% vs. 15.5%). Nevertheless, in all cases, we confirmed that the vast majority of reactions in both SCIT and SLIT were mild.
In the univariate analysis, SCIT with grass pollen and epithelia had a higher risk for AE compared with other allergen sources.
However, these associations were lost in the multivariate analysis, in which only the route of administration remained significant. Grass extract has also been associated with a higher rate of AE in other reports too. 10 Even though more than 50% of the patients were polysensitized, the majority (90%) received single allergen immunotherapy, reflecting the 'European' approach to AIT, in contrast to the US approach of prescribing mixtures. 30 Although there was no difference in the rate of AE in our population between those receiving mixtures or single allergen, it is still controversial whether treatment with mixtures can be approximately safe. 35,36 We found no significant differences between natural and allergoid preparations or in regard to different adjuvants, probably reflecting the small number of overall AEs, and possibly, the fact that our population consisted of children and adolescents. The adult population will be analyzed separately in the forthcoming papers.
In spite of the 250 recorded AE, discontinuation of immunotherapy was decided in only 4 patients (0.46%), further supporting the finding that the treatment was well-tolerated and AEs were perceived as mild from both parents and the children themselves but also by physicians.
The current report has some limitations. The variability between centers, although a strength, can also be a limitation when comparing different small subsamples. For example, the proportions of SCIT and SLIT, but also different preparations vary considerably in our registry.
SLIT follow-up is usually different from SCIT. Inclusion criteria were not identical as each country has its own health system and regulations. However, having included different clinical settings, patient populations, physician's educational background and AIT protocols and products, according to real-life clinical practice, empowers this study findings and offers a large amount of real-world evidence.
AIT remains a key feature of personalized medicine for allergic disease treatment, continuously evolving and comprises a major part of an allergist's daily practice worldwide. Considering that it is crucial to shape future recommendations based on broad applicable and credible data, such as those from registries with a prospective approach. 37 The design and setup of ADER allows data entering in a simple and effective manner that permits easy expansion in other countries. In addition, we recorded SRs using the harmonized MeDRA terminology 19 as in the EAASI, which is a strength. The use of MeDRA terminology, recommended also by EMA, offers a uniform system of collecting safety data that enable comparing results from different reports and limits recording biases.
In conclusion, this study demonstrates the safety profile of SCIT and SLIT treatments in children and adolescents. While SLIT results in significantly less AE than SCIT, both approaches are safe and well tolerated in specialized centers across different countries.